Uses and limitations of the restricted mean survival time: illustrative examples from cardiovascular outcomes and mortality trials in type 2 diabetes

The Restricted Mean Survival Time (RMST) has been advocated as an alternative, or supplement, to the hazard ratio (HR) for reporting the effect of an intervention in a randomized clinical trial. The RMST difference allows quantifying the postponement of an outcome over a specified (restricted) time interval and corresponds to the difference between the areas under the two survival curves for the intervention and the control arm.In this article, we present examples of its uses in a research and a clinical context. First, we show how the RMST difference can answer research questions about the efficacy of different treatments. We present estimates for the effects of pharmacological or strategy-driven glucose-lowering interventions for adults with type 2 diabetes from 36 trials and 9 follow-up studies reporting cardiovascular outcomes and mortality. We show how these measures can be used to mitigate uncertainty about the efficacy of intensive glucose control. Second, we demonstrate how the RMST difference can be used in the setting of a clinical consultation to guide the decision to start or discontinue a treatment.We then discuss the advantages of the RMST over the absolute risk difference, the number needed to treat, and the median survival difference. We argue that the RMST difference is both easily interpretable and flexible in its application to different settings. Lastly, we highlight its major limitations, including difficulties in comparing studies of heterogeneous designs and in inferring the long-term effects of treatments using trials of short duration, and summarize the available statistical software for calculating the RMST.</div

Efficacy of Low- and Very-Low-Energy Diets in people with Type 2 Diabetes Mellitus: A systematic review and meta-analysis of interventional studies.

AIMS: To systematically review and quantify the weight loss achieved by Low- and Very-Low-Energy Diets in people with type 2 diabetes mellitus. MATERIALS AND METHODS: Studies reporting the effects of diet-only interventions up to 1600kcal/day in people with type 2 diabetes mellitus were searched in MEDLINE, EMBASE, CINAHL until July 2018. Changes in the primary (body weight and body mass index) and secondary (HbA1c, blood lipids) outcomes according to energy restriction and duration of diet were modelled using restricted cubic splines. RESULTS: Forty-four studies (3817 participants) were included. The overall quality of the evidence was moderate and limited to short-term interventions up to four months. Baseline mean weight and body mass index were 92.1kg and 36.6kg/m2 . Very-Low-Energy Diets of 400kcal/day led to 5.4% weight loss at two weeks, increasing to 17.9% at three months. More modest reductions of 7.3% were observed on Low-Energy Diets of 1200kcal/day and 2.0% on 1600kcal/day after three months. No clear patterns emerged for secondary outcomes. Publication bias was significant for primary outcomes. CONCLUSIONS: High-quality studies are required to support evidence-based Low- and Very-Low Energy prescription in people with type 2 diabetes. Available evidence would suggest variable reduction of body weight, ranging from 2% to 18%, after three months of Low- and Very-Low-Energy Diets

Efficacy and tolerability of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: A systematic review and network meta‐analysis

Aim: To compare the efficacy and tolerability of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes.Materials and methods: Electronic databases were searched from inception to 24th April 2019 for randomised controlled trials reporting change in glycated haemoglobin (HbA1c) at approximately 24 and/or 52 weeks for SGLT-2is and/or GLP-1RAs (classified as short- and long-acting). Bayesian network meta-analyses were conducted to compare within and between SGLT-2i and GLP-1RA classes for cardiometabolic efficacy and adverse events (PROSPERO registration number: CRD42018091306). Results: 64 trials (53 trials of 24 weeks; 7 trials of 52 weeks; 4 trials of both 24 and 52 weeks), comprising of 31,384 participants were identified. Compared to placebo, all treatments improved HbA1c. Long-acting GLP-1RAs reduced HbA1c compared to short-acting GLP-1RAs and SGLT-2 is, with semaglutide showing greater reduction compared to placebo (24 weeks: -1.49% (95% credible interval [CrI]: -1.76, -1.22), 52 weeks: -1.38% (-2.05, -0.71)) and all other treatments. Long-acting GLP-1RAs showed benefits in body weight and waist circumference reduction, while SGLT-2 is reduced blood pressure. SGLT-2is showed increased odds of genital infection in comparison to long-acting GLP-1RAs (odds ratio (95% CrI): 5.26 (1.45, 25.00)), while GLP-1RAs showed increased odds of diarrhoea in comparison to SGLT-2is (short-acting GLP-1RAs: 1.65 (1.09, 2.49), long-acting GLP-1RAs: 2.23 (1.51, 3.28)). No other differences were found between SGLT-2is and GLP-1RAs in adverse events. Conclusion: Long-acting GLP-1RAs showed superiority in reducing HbA1c levels, body weight and waist circumference. SGLT-2 is showed reductions in blood pressure levels. This review provide essential evidence to guide treatment recommendations in the management of type 2 diabetes<br